tbuckley/cabot-search huggingface dataset:
Abstract 12021: Investigation of the Role of Long Non-Coding RNA H19 on Endothelial to Mesenchymal Transition in Aortic Valve Stenosis
Authors: Katharina Maus, M. Rabiul Hosen, Felix Jansen
Journal: Circulation (2022)

Background: Endothelial to mesenchymal transition (EndMT) is a transdifferentiation process of cells that is associated with the development of aortic valve stenosis (AVS) in adulthood. It was shown that long non-coding RNAs are dysregulated in this process and might play a crucial role in EndMT-mediated AVS. Here we aim to elucidate the role of long non-coding RNA H19 (LncRNA H19) in the pathogenesis of EndMT-related AVS. Methods and Results: RNA sequencing of aortic valve tissue explanted from AVS-patients with coronary artery disease (CAD) revealed that H19 was significantly dysregulated. EndMT was induced in vitro in vascular and valvular endothelial cells (VECs) via TNFα and TGFß+IL1ß stimulation and expression of endothelial marker genes vWF and eNOS and mesenchymal marker genes αSMA , SM22 , Vimentin and SNAI2 was confirmed by RT-qPCR. Loss of function of H19 followed by EndMT induction demonstrated distinct changes in gene expression profile and protein levels which were detected by qRT-PCR, immunoblotting, and immunofluorescence. Further experiments indicate that loss of H19 may promote EndMT. Functional assays in vascular and valvular endothelial cells suggested that H19 is a critical regulator of angiogenic sprouting and migration. To unveil the specific molecular signature in angiogenesis a RT 2 profiler array was performed to identify the regulation of angiogenesis with 84 angiogenesis-related genes. Our assay revealed JAG1 as a potential dysregulated candidate with a 4.43-fold regulation. Further molecular mechanism will be investigated via identification of binding partners and downstream targets of H19 in EndMT by using primary cells and VECs. Conclusion: Our data suggests that H19 might play a role in EndMT in context of AVS. Further investigation by using a murine model of AVS should confirm the H19-mediated of EndMT in the development of AVS.
Abstract 12020: Overestimation of the Ischemic Area-at-Risk Despite Partial Resolution of Myocardial Edema Twenty-Four Hours After Myocardial Infarction in Swine
Authors: Tyler J Rolland, Alex J Fees, Brian R Weil
Journal: Circulation (2022)

Objective: Accurate delineation of the ischemic area-at-risk (AAR) is essential for precise quantification of tissue salvage following myocardial infarction (MI), but time-dependent changes in tissue composition may influence the AAR when it is measured after reperfusion. Based on evidence that post-MI edema declines 24 hours after reperfusion, we utilized serial contrast-enhanced computed tomography (CT) to determine if this is an optimal timepoint for retrospective assessment of the AAR in swine. Methods: Swine (n=7) were subjected to a 75-minute LAD occlusion, during which an initial CT scan was performed to assess the pre-reperfusion AAR. A second CT scan was performed during re-occlusion of the LAD 24 hours later to determine the post-reperfusion AAR. Echocardiography was performed at baseline as well as 1 hour and 24 hours after reperfusion to assess end-diastolic wall thickness (EDWT) as an index of post-MI edema. Infarct size was quantified via post-mortem TTC staining and expressed relative to pre- vs. post-reperfusion AAR values. Results: Dynamic changes in EDWT were observed throughout the reperfusion period, consistent with marked edema early after reperfusion and a subsequent decline 24 hours later ( Table; top ). Despite partial resolution of edema 24 hours after reperfusion, a significant ~25% increase in the AAR was observed at this timepoint vs. pre-reperfusion values ( Table; bottom ). As a result, infarct size differed significantly if expressed relative to the pre-reperfusion AAR (91.7 ± 9.2 %) vs. the post-reperfusion AAR (70.9 ± 8.3 %, p&lt;0.01). Conclusion: The ischemic AAR is overestimated relative to pre-reperfusion values when measured retrospectively 24 hours after reperfusion, despite partial resolution of myocardial edema at this timepoint. These results illustrate how variability in post-infarction edema may complicate the assessment of relative infarct size and myocardial salvage when the AAR is measured after reperfusion.
Abstract 12053: Worsening Tricuspid Regurgitation After Leadless Pacemaker Implantation Leads to Higher Hospitalization for Heart Failure
Authors: Kevin Lee, Mark Metzl
Journal: Circulation (2022)

Introduction: One of the many purported benefits of a leadless pacemaker (LP) is avoidance of interaction with the tricuspid valve, decreasing tricuspid valve dysfunction from chronic injury resulting from contact with transvenous leads. Data suggests that 31-38% of patients develop worsening tricuspid regurgitation (TR) after transvenous pacemaker implantation. However, some recent data suggest that LP therapy is also associated with a higher incidence of worsening TR, possibly similar to transvenous pacemakers. We present data from a large community-based health system on the incidence of worsening TR after LP implantation and its clinical implications. Methods: A total of 256 patients (mean age 80±10 years, 61% male) who received Micra leadless single chamber pacemaker devices at the NorthShore University HealthSystem between April 2017 and November 2021 were retrospectively reviewed. A total of 103 patients (40%) received both a transthoracic echocardiogram within 6 months pre-implantation and 6 months post-implantation. Characterization of TR and heart failure hospitalization were gathered through chart review. Results: Of the 103 patients, 39 (38%) were found to have worsening of their TR after LP implantation when compared to before. Of the patients with worsening TR, 18 (46%) required hospitalization for heart failure within 12 months, compared to 15 (23%) without worsening TR ( X 2 = 5.7, p = 0.02). Conclusions: LP implantation is associated with comparable levels of worsening TR (38%) when compared to transvenous pacemakers. Worsening TR is associated with increased heart failure hospitalization within 12 months. More data is required to establish the reasoning behind the comparable levels of worsening TR in LP given the lack of mechanical interaction with the tricuspid valve apparatus.
Abstract 12604: Coronary Artery Calcium Score Determined From Pre-Ablation Pulmonary Vein Computed Tomography Allows for Diagnosis of Coronary Artery Disease and Improved Atherosclerotic Cardiovascular Disease Risk Prediction
Authors: Christopher Nmai, Arun Manmadhan, Gaurav Sharma, Sean P Heffron
Journal: Circulation (2022)

Objective: Coronary artery calcification (CAC) is a useful adjunct for atherosclerotic cardiovascular disease (ASCVD) risk stratification and can influence preventive strategies. However, CAC screening is infrequently done, even among cardiology patients. Ancillary imaging, for example pulmonary vein CT (CTPV) performed prior to atrial arrhythmia ablation, may allow for CAC quantification. Our goal was to assess CAC prevalence on pre-ablation CTPVs and to assess how this information could influence risk stratification. Methods: Patients undergoing atrial arrhythmia ablation at NYU from 4/1/18 to 4/30/19 were identified and all available medical records reviewed. CTPVs were reviewed and CAC graded semi-quantitatively (0, 1-9, 10-99, 100-399, 400-999, 1000+). 10-yr ASCVD and MESA scores were calculated for patients without known ASCVD. Results: 739 patients underwent ablations and 660 had CTPV available for assessment. Mean age was 63.4 ± 11.4 years, 33.9% were female, and 17.1% had a history of ASCVD (prior MI, CVA/TIA, CAD, PAD). CAC was present in 62% of patients, including 57.2% without ASCVD history (22.3% of these had CAC ≥100). Complete data for the calculation of 10-year AHA/ACC and MESA risk scores were present in 27.9% and 32.4%, respectively. MESA CHD risk score allows for the incorporation of CAC for improved predictive capacity. Median MESA risk was 6.5% without and 6.7% with median CAC included. Incorporating CAC into MESA risk decreased risk in 110 patients (79 of these had CAC &lt;10), and increased risk in 102 patients (101 had CAC ≥10) ( Figure ). AHA/ACC ASCVD risk distribution is displayed in Figure. Guidelines recommend consideration of statins in those with ASCVD risk &lt;7.5% and non-zero CAC. 52.4% of patients with ASCVD risk &lt;7.5 had non-zero CAC ( Figure ) with 18.2% on a statin at the time of their procedure. Conclusion: Quantification of CAC on CTPV can provide a means to diagnose CAD, improve risk stratification and impact primary preventive treatment.
Abstract 11944: Surfactant Protein a Promotes Smooth Muscle Cell Phenotype Modulation Through Inhibiting the Myocardin-Smad3 Interaction
Authors: Skylar D King, Dunpeng Cai, Mikayla M Fraunfelder, Shiyou Chen
Journal: Circulation (2022)

Vascular smooth muscle cell (SMC) transition from a differentiated to dedifferentiated phenotype and subsequent neointima formation/vascular remodeling plays a critical role in the development of a number of vascular diseases such as atherosclerosis, restenosis after angioplasty or bypass, diabetic vascular complications, arteriopathy transplants, asthma and cancer. However, mechanisms that regulate SMC phenotype modulation and neointima formation are not completely understood. We have found that Surfactant protein A (SPA), an innate immune system collectin that reduces membrane surface tension and protects lung function during exhalation, is critical for SMC phenotype and vascular modeling. SPA is induced during SMC phenotypic modulation and injury-induced vascular remodeling in both rat and mouse carotid arteries. Knockdown of SPA increased contractile protein expression while enhancing the expression of Myocardin and TGF-β1 in SMCs. Moreover, SMCs from SPA knockout mice had increased Smad3 phosphorylation which was blocked by TGF-β1 neutralizing antibody. To understand the contribution of SMC SPA to vascular remodeling, we generated SMC specific SPA-deficient (SPAsm -/- ) mice with hypercholesteremia by injection of AAV-PCSK9. By using mouse carotid artery wire-injury model, we found that SPA deficiency in SMCs markedly inhibits neointimal formation and the Myocardin-Smad3 interaction in the injured artery. Our data demonstrated that SPA mediates proliferative/synthetic phenotype and neointimal hyperplasia by blocking Myocardin-Smad3 interaction.
Abstract 11977: Dapagliflozin Downregulates Adrenal G Protein-Coupled Receptor-Kinase-2 to Exert Sympatholysis in Heart Failure
Authors: Anastasios Lymperopoulos, Jennifer Maning, Natalie Cora, Celina M Pollard, Victoria L Desimine, Gianluca Iacobellis
Journal: Circulation (2022)

Introduction: Dapagliﬂozin is a sodium-glucose co-transporter (SGLT)-2 inhibitor exerting several cardiorenal protective effects independently of blood glucose regulation. Adrenal G protein-coupled receptor kinase (GRK)-2 upregulation is a major driver of circulating catecholamine (CA) elevation and sympathetic nervous system (SNS) hyperactivity, especially in heart failure (HF). GRK2 severely dysregulates adrenal sympatho-inhibitory α 2 -adrenergic receptors (ARs), leading to unchecked, chronically elevated CA secretion. Hypothesis: SGLT2 inhibition with dapagliﬂozin lowers SNS hyperactivity in part by opposing adrenal GRK2 actions. Methods: We used the rat pheochromocytoma PC12 cell line expressing human α 2A AR, as well as freshly isolated adrenal glands from rats treated with dapagliﬂozin in vivo. Results: Dapagliﬂozin treatment for 7 consecutive days (20 mg/kg/d in drinking water) led to a signiﬁcant reduction in blood circulating NE levels (217+67 pg/ml, n=6), compared to control, vehicle-treated rats (363+77 pg/ml, n=6, p&lt;.05), suggesting reduced SNS activity. This was accompanied by reduced GRK2 and tyrosine hydroxylase (TH) mRNA and protein levels in dapagliﬂozin-treated rat adrenals vs. vehicle-treated animal-derived glands, indicating reduced adrenal CA synthesis and secretion. Finally, adrenal α 2 AR density was higher in dapagliﬂozin- vs. vehicle-treated rats(51.3+7.3 vs. 26.1+8.1 fmol/mg of protein, respectively; n=12 glands from 6 animals per group, p&lt;.05). GRK2 and TH downregulation were also observed in PC12 cells treated with 5 μM dapagliﬂozin for 24 hours. Importantly, α 2 AR-dependent inhibition of CA secretion was markedly enhanced 24 hrs post-dapagliﬂozin application. This was due to reduced GRK2-dependent receptor desensitization induced by dapagliflozin, since this effect was abolished in PC12 cells overexpressing GRK2. Conclusions: Dapagliﬂozin exerts a sympatholytic action in the adrenal medulla via downregulation of both TH, thus reducing CA biosynthesis, and GRK2, thus reducing α 2 AR desensitization to lower CA secretion. This adrenal-mediated sympatholysis may be part of the increasingly apparent cardiovascular benefits of SGLT2 inhibitors in human HF irrespective of diabetic status.
Abstract 11884: Comparison of Investigator-Reported and Adjudicated Events From SOLOIST-WHF and SCORED
Authors: Prakriti Gaba, Deepak L Bhatt, Philippe G Steg, Phillip Banks, Michael J Davies, Michael Szarek, Bertram Pitt
Journal: Circulation (2022)

Introduction: Sotagliflozin reduced investigator reported cardiovascular (CV) deaths, hospitalizations for heart failure (HHF), and urgent visits for heart failure (UVHF) in SOLOIST-WHF and SCORED. The objective of the present analysis was to determine if the treatment effects on adjudicated events were consistent those on investigator reported events in each trial. Methods: SOLOIST-WHF and SCORED were Phase 3, multicenter, randomized, double-blind, trials evaluating sotagliflozin versus placebo in 1,222 patients with type 2 diabetes (T2D) admitted for a worsening heart failure event and in 10,584 patients with T2D, chronic kidney disease, and other CV risk factors, respectively. The primary composite endpoint was a composite of CV death, HHF, and UVHF. Treatment effects on investigator reported events and available adjudicated events were estimated in proportional hazards models. Results: Rates of the investigator reported primary composite endpoint were higher in the SOLOIST-WHF trial compared with the SCORED trial. However, relative risk reductions for the investigator reported primary composite endpoint were similar between SCORED (0.67[0.53, 0.85]) and SOLOIST-WHF (0.75[0.63, 0.88]). All components of the endpoint positively contributed to the overall outcome, with HHF having the largest effect. When compared with adjudicated outcomes, results were generally similar between the primary and sensitivity analyses using various combinations of total or first occurrences (Figure). Conclusions: Sotagliflozin led to consistent and significant reductions in CV death, HHF, and UVHF in both randomized trials, as determined by blinded investigator-reported assessment as well as by independent, blinded adjudication. These results support the overall robustness of the findings for both trials.
Abstract 12075: Extracellular Vesicle Cargo Long-Noncoding RNAs Are Dynamic Biomarkers in Acute Decompensated Heart Failure
Authors: Priyanka Gokulnath, H Immo Lehmann, Michail Spanos, Quanhu Sheng, Rodosthenis Rodosthenous, Emeli Chatterjee, Elizabeth Hutchins, Guoping Li, Ashley Mingyi Wang, kendall Van Keuren-Jensen, Ravi V Shah, Saumya Das
Journal: Circulation (2022)

Introduction: Acute decompensation is associated with increased long-term mortality in patients with heart failure (HF). Biomarkers of acute HF that are dynamic during decongestion may provide physiologic insight for this observation. We hypothesized that long-noncoding RNAs (lncRNAs) and mRNAs in extracellular vesicles (EVs) not only mark different types of HF, but also may be dynamically altered with decongestion across physiologically important pathways. Methods: RNA sequencing was performed on plasma-derived EVs in acute HF patients (7 HFpEF; 7 HFrEF) at hospital admission (V1) and at discharge (V2) along with 9 controls without HF. Differential expression analysis was performed using DESeq2 across groups and time-points. Transcripts were prioritized by fold change (±1.5) and statistical significance (&lt;5% FDR). We subsequently validated targets in EVs from 182 additional patients (24 control; 86 HFpEF; 72 HFrEF). Results: Between HF and control patients, 138 lncRNAs and 147 mRNAs were different (Fig a,b). LncRNAs were confirmed to be exclusively present in EVs. Of 13 targets investigated in our validation cohort, 5 lncRNAs and 6 mRNAs were significantly different between control and HF (age, sex-adjusted; Fig c). Pairwise comparisons between EV RNAs at hospital admission versus decongestion revealed a significant change in 4 lncRNAs (Fig d,e ) that was independent of weight change during hospitalization. Notably, distinct fragments derived from these transcripts were noted in HF versus control groups. Conclusions: The plasma EV transcriptome is significantly altered in patients with acute HF. Plasma EV-derived lncRNA fragments demarcate congestion and decongestion better than mRNAs, may be markers for pathophysiologically relevant pathways independent of volume status, and may provide additional prognostic information.
Abstract 12297: Kissing Left Atrial Appendage Closure Devices for Peri-Device Leak
Authors: Bridget Lee, Jamarcus Brider, Brandon Doty, Feross Al-Hindi, Devi Nair
Journal: Circulation (2022)

Introduction: Left atrial appendage closure (LAAC) therapy is approved for stroke prevention in nonvalvular atrial fibrillation (AF) for patients intolerant in long term oral anticoagulation (OAC). Peri-device leak (PDL) is the achilles heel to optimal LAAC and increases stroke risk. Here, we describe the novel use of a second LAAC device for closure of a large PDL in a bilobar appendage. Case: A 66-year-old male with a history of nonvalvular AF with recurrent bleeding on OAC with Watchman 2.5 implant six years prior, presented to our facility for a repeat AF ablation. Pre-procedural imaging showed a PDL of 12 mm with an uncovered posterior lobe, with the Watchman 2.5 covering only the anterior lobe of the appendage. The PDL was closed with a 20 mm Amulet device delivered through a steerable sheath abutting the existing Watchman 2.5 device. The steerability of the sheath allowed for optimal placement of the Amulet device to allow for complete closure. Patient was discharged home on six weeks of dual antiplatelet therapy. Discussion: In our case, a second LAAC device was chosen due to the large size of the PDL. Smaller leaks can be closed using endovascular coils and/or occluder plugs. Larger leaks require additional consideration for closure strategies such as a second LAAC device Conclusions: Our case is the first reported case utilizing a second LAAC device for PDL closure alongside the first device. Steerability of the new Amulet sheath allowed for optimal device placement for complete closure. Additional research is needed on how PDL’s should be addressed for optimal LAAC. Figure 1: Imaging showing PDL into uncovered posterior lobe Figure 2: Complete LAAC with kissing Watchman 2.5 and Amulet
Abstract 12033: The IFNb-Gbp7 Pathway Plays an Important Role in Activating Cardiomyocyte Genes
Authors: Xinghua Wang, Syeda Baksh, Richard E Pratt, victor dzau, Conrad Hodgkinson
Journal: Circulation (2022)

We discovered that reprogramming scar fibroblasts into cardiomyocytes requires activation of innate immunity. Recently, we found that innate immunity exerts its influence on fibroblast to cardiomyocyte reprogramming via the RNA-sensing receptor Rig1. However, the mechanism was not identified. Rig1 activation, whether by classical agonists or via rationally designed RNA molecules, enhanced the efficacy of cardiac reprogramming with cardiomyocyte-specific gene expression increasing by 10 to 50 fold (Actn2, Myh6, Tnni3; N=6; P&lt;0.01) and cardiomyocyte generation increasing 5 fold (N=3, P&lt;0.01). RNA-seq indicated that Rig1 activation in fibroblasts induced IFNβ signaling pathways. To verify a role for IFNβ, knockdown studies were performed. Transfection of fibroblasts with an IFNβ targeting siRNA completely ablated the effects of Rig1 agonists with respect to cardiac reprogramming (N=5, P&lt;0.01). Further studies with specific blocking antibodies and media replacement showed that IFNβ was acting in a paracrine manner. To determine the mechanism whereby IFNβ regulated cardiomyocyte gene expression, we screened a number of candidates identified in the RNA-seq: Ccl5, Ccl10, Gbp5, and Gbp7. Knockdown of Ccl5, Ccl10, or Gbp5 had no effect on the ability of IFNβ to enhance cardiac reprogramming efficacy. In contrast, the ability of IFNβ to enhance cardiac reprogramming was lost in fibroblasts lacking Gbp7 (N=5, P&lt;0.01). To conclude, the IFNβ-Gbp7 pathway plays a critical role in cardiac reprogramming. Manipulation of the IFNβ-Gbp7 pathway may enhance the effectiveness of cardiac reprogramming in vivo.
Abstract 11083: Post-Infarction Cardiac Protection by Gut Butyrate-Producers
Authors: Hung-Chih Chen, Patrick C Hsieh
Journal: Circulation (2022)

Background The gut microbiota and their metabolites have been shown to contribute to the development of coronary artery diseases. However, little is known about their roles in post-injury cardiac repair. Here, we investigated the gut microbiota and plasma metabolomes distinct in patients with ST-elevation myocardial infarction (STEMI), and explored their roles on adaptive responses, using germ-free (GF) mice and nonhuman primate models. Methods We recruited 70 controls and 77 coronary angiogram-confirmed STEMI patients, and collected their stool and plasma. The stool and plasma of STEMI patients were collected immediately following percutaneous coronary intervention (PCI, STEMIT1) and again at 28 days after PCI (STEMIT2). We used 16S V3-V4 rRNA NGS and shotgun metagenomics to map the gut microbiota and both NMR and LC-MS metabolomics to profile the plasma metabolites. To determine the role of the gut microbiota and their metabolites on post-injury cardiac repair, we inoculated identified bacteria in GF mice and treated specific pathogen free mice with candidate metabolites. Moreover, we validated the microbiome and metabolomics findings in a nonhuman primate coronary ischemia-reperfusion (IR) injury model. Results The 16S V3-V4 rRNA NGS and shotgun metagenomic analysis revealed an enrichment of butyrate-producing bacteria in STEMIT1, as compared to STEMIT2 or to control cases. Fecal microbiome transplantation of STEMI samples in GF mice deteriorated host post-injury cardiac function, showing reduced left ventricle ejection fraction and cardiac mechanics. Moreover, plasma ketogenesis increased in the STEMI patients using NMR and LC-MS metabolomics. The protective effect of butyrate was more profound with intact commensal gut flora. Furthermore, inoculation of butyrate-producers in GF mice elevated plasma ketone body and better preserved post-injury cardiac function. Agreed with the clinical finding, we observed injury-induced elevation of gut butyrate-producers and plasma ketone bodies in the nonhuman primate IR model. Conclusion This study demonstrates the pivotal role of gut butyrate-producers and the derived ketogenesis in post-injury cardiac repair, which may lead to new prevention strategies and treatment for heart failure.